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Hong kong case studies

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    Hong kong case studies Hong kong case studies Presentation Transcript

    • Audience Response Cases Donna M. Weber, MD Professor of Medicine, Department of Lymphoma/Myeloma
    • Case 1 • 59 yr old male • 7/2012: Dyspnea, chest pain, pain between shoulders • 8/2012: Cardiac work-up: Stent placement • 9/2012: Pain continued: MRI spine: T7 compression, C5-6 and C3-4 encroachment on neural foramina • 9/18/2012: Hospitalized for respiratory infection: Hgb 8.3 g/dL, creatinine 2.03, Ca++ 12.3 mg/dL, albumin 1.8 g/dL, hydrated sent home
    • Case 1 • Bone marrow 85% CD38, CD138, CD56, λ +, κ – PC T. Protein 12.4 g/dL, Albumin 3.0 g/dL, M-protein 5.7 g/dL: IgG λ, Bence Jones Protein 1250 mg/day Free λ 2420 mg/L Free κ 14.6 mg/L Free κ: λ 0.01 β2M 44.7 mg/L Alb 3.0g/dL: ISS stage III • Bone survey: lytic lesions skull, ribs, T7 compression • Hgb 10.9 g/dL, Plt 206 k/μL , WBC 7.9 k/μL, 3% plasma cells, BUN 53 creatinine 4.69, Ca++ 13.1 mg/dL, albumin 3.0 g/dL, uric acid 13.3 • Cytogenetics: t(4;14), del 13, del 1q
    • Case 1 (Questions) What would you do first? 2. Chemotherapy/Immunotherapy 3. Chemo/Immunotherapy + Dialysis 1. Dialysis
    • High Cut Off Hemodialysis (HCO-HD) • 2005: 97 pts randomized to conventional therapy or conventional therapy w/ 5-7 plasma exchanges (stratified by dialysis) w/ no benefit in mortality, dialysis dependence, or GFR < 30 ml/min at 6 mos. Clark et al: Ann Intern Med 143: 777-84, 2005 • 2010: 27 pts MM w/ HD dependence (CrCl < 15 ml/min) 19 pts had biopsy proven cast-nephropathy and received combination chemo and FLC removal by HCO-HD). 8 hrs/day x 5 days then 8 hrs q.o.d. x 12 days or more 13/19 pts achieved sustained reduction FLC 6 pts not achieving sustained reduction had chemo interrupted Dialysis equally effective, difference due to FLC production rates Uninterrupted Baseline FLC: D12 FLC = 1% Interrupted Baseline FLC: D12 FLC = 266% 14/19 became dialysis independent Hutchison et al: Clin J Am Soc Nephrol 4: 745-54, 2009
    • Case 1: Results With Therapy Initiation Chemo held temporarily due to infection
    • Case 1 (Questions) What would be the best induction therapy? 2. Lenalidomide and dexamethasone (once weekly) 3. Bortezomib and dexamethasone (day of and after B) 4. Bortezomib, melphalan and prednisone 5. Bortezomib, cyclophosphamide, dexamethasone 1. Thalidomide and dexamethasone (once weekly) 6. Bortezomib, lenalidomide, dexamethasone
    • Criteria for Renal Response Reversibility of Renal Failure Renal Response Sustained (lasting 2 months) improvement of creatinine clearance Complete (CRrenal) Improvement of CrCl from < 50 ml/min to > 60 ml/min Partial (PRrenal) Improvement of CrCl from < 15 ml/min to 30-59 ml/min Minor (MRrenal) Improvement of CrCl from < 15 ml/min to 15-29 ml/min OR 15-29 ml/min to 30-59 ml/min Dimopoulos et al, Clin Lymphoma Myeloma 2009:9:302-6
    • Considerations for Induction Therapy Using Novel Agents in Patients with Renal Failure Thalidomide Lenalidomide CarfilzomibConsideration Bortezomib No Yes No Renal metabolism No No Possible Possible, Avo idable Renal Toxicity No ? ? ? Efficacy for Induction in Renal Failure ? Hyperkalemia Cytopenias None Additional Toxicity in Renal Patients None
    • CC I-B B-B 32 47 17 Parameter n 29.2 26.9 20.6Med. CrCl (ml/min) 53 53 76%CrCl < 30ml/min % Renal Response 59 79 94> MRrenal 41 45 71CRrenal 47 51 82> PRrenal p0.04 Roussou et al, Leukemia Research 2010:9: 1395-1397 Reversibility of Renal Failure Newly Diagnosed 1.8 1.6 0.69Med. Mos to Response p0.007 9 19.1 23.5%Renal Response w/o MM Response CC = Combination Chemotherapy (VAD/VAD-like, Melphalan + HD Dex) I-B = IMiD-Based Thalidomide or lenalidomide + HD Dex +/- cyclophosphamide/melphalan B-B = Bortezomib-based + HD Dex
    • Lenalidomide Lenalidomide Dose (mg) Creatinine Clearance (m/min) 10 mg/Day> 30 - 50 5 mg/D after dialysis On dialysis 15 mg q48 hours < 30, NOT on dialysis Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf
    • Case 2 • 36 yr old female • 2/2010: Rt Chest wall pain during pregnancy Did not resolve after pregnancy
    • • 3/2010: Rt. Rib resection: + CD38 +CD56 +Kappa Plasma cells • 3/2010: Preoperative creatinine 0.8 mg/dL Postoperatively 5.1 mg/dL Dexamethasone 40 mg x 1 Transfer to MD Anderson Cancer Center Case 2 • Hgb 7.5 g/dL, Plt 611 k/μL , WBC 10.2 k/μL, BUN 48 creatinine 4.1mg/dL, Ca++ 10 mg/dL, albumin 4.1 g/dL, uric acid 7.5, potassium 5.5 meq/L, phosphorus 5.5 mg/dL
    • Case 2 • Bone survey: Rib lesion + Small lytic lesions bilateral femora + humeri • Bone marrow 50% CD38, CD138, CD56, λ -, κ + PC T. Protein 7.3 g/dL, Albumin 4.3 g/dL, M-protein 0.2 g/dL, IgG K, Bence Jones Protein 4925 mg Kappa/d Free λ 10.4 mg/L Free κ 15,300 mg/L Free κ: λ 1471.5 β2M 9.9 mg/L Alb 4.3g/dL: ISS stage III • Cytogenetics: Deletion 13 and Deletion 17p13.1
    • Case 2 What Would Be the Best Induction Therapy? 1. Lenalidomide and dexamethasone (once weekly) 2. Bortezomib and dexamethasone (day of and after B) 3. Bortezomib, melphalan and dexamethasone 4. Bortezomib, cyclophosphamide, dexamethasone 5. Bortezomib, lenalidomide, dexamethasone 6. Bortezomib, doxorubicin, dexamethasone (PAD)
    • Case 2 Would you proceed with myeloablative therapy and stem cell transplant after successful induction? 2. No 1. Yes
    • Case 2 After successful induction therapy +/- myeloablative therapy and autologous stem cell transplant what maintenance therapy (if any) would you use? 2. Lenalidomide 1. None 3. Bortezomib 4. Other
    • Avet-Loiseau H et al. JCO 2010;28:4630-4634©2010 by American Society of Clinical Oncology Bortezomib Induction: Impact in del 17p Deletion 17p (n = 54) No deletion 17p (n = 453) Bortezomib + Dex x 4 cycles
    • ARM A ARM BParameter Med. PFS (mos) 12 22 (26.2)Deletion 17p 17 69Deletion 17p 8 62Deletion 17p in >60%PC 3 yr OS (%) Sonneveld et al, J Clin Oncol 30: 2946-55, 2012 Bortezomib Induction & Maintenance: Hovon-65/GMMG-HD4 ARM A: VAD + CyAD + HDM/AuSCT + Thal 50 mg po qD x 2yrs ARM B: P(Bortezomib)AD + CyAD + HDM/AuSCT + Bortezomib 1.3 mg/M2 q 14d x 2yrs Neben et al, Blood 119 (4): 940-8), 2012 80 85No Deletion 17p p.01(.02) p.028 p.48 p.037 12 25.7Deletion 17p in >60%PC p.017 24 >54Deletion 17p Med. OS (mos) p.003 NS NSNo Deletion 17p
    • Cycle 1 Bortezomib, Cyclopho sphamide, Dexametha sone Days 1-4, 9- 12, 17-20 Cycles 2-4 Bortezomib, Cyclophospha mide, Dexamethasone D1,8,15,22 High-Dose Melphalan + AuSCT Bortezomib Maintenance q2wks
    • Bortezomib, lenalidom ide, Dexamethasone HD Melphalan + AuSCT Bortezomib, lenalidom ide, Dexamethasone HyperCVAD + bortezomib VDT-PACE lenalidomide Thalidomide, Dexamet hasone Mandibular soft tissue mass despite improved protein Bortezomib, Dexamet hasone + XRT Pt decided steroid + XRT only + supportive care
    • Case 3 • 72 yr old male • 12/2006: Rib pain • 2/2007: Sharp burning pain from Rt hip radiating to leg
    • Case 3 • Bone marrow 30% +CD38, +CD138, -CD56, λ -, κ + PC T. Protein 7.5 g/dL, Albumin 3.0 g/dL, M-protein 2.8 g/dL: IgG λ, Bence Jones Protein 0 mg/day Free λ 4.39 mg/L Free κ 8.27 mg/L Free κ: λ 1.884 β2M 1.8 mg/L Alb 3.0g/dL: ISS stage II • Bone survey: T12 lesion + osteoporosis • Hgb 12 g/dL, BUN 53 creatinine 1.4mg/dL, Ca++ 9.1 mg/dL • Radiation 20 Gy Thalidomide 200 mg daily + Dexamethasone Weekly Second opinion at MD Anderson
    • Case 3 HDM + AuSCT Thalidomide + Dexamethasone
    • • 4/2007-7/2007: Thalidomide + Dexamethasone Developed Grade 2 neuropathy during induction. Case 3 • 7/2007: HDM + AuSCT: Worsening of neuropathy. VGPR: No Maintenance; neuropathy persists, but improved to grade 2 without pain.
    • Case 3 What would you use for Relapse? Thalidomide + Dexamethasone HDM + AuSCT
    • Case 3 What would you use for Relapse? 2. Lenalidomide and dexamethasone (once weekly) 3. Bortezomib and dexamethasone (day of and after B) 4. Lenalidomide-based 3 drug combination 1. Thalidomide and dexamethasone (once weekly) 4. Bortezomib-based 3 drug combination 5. Carfilzomib 5. Pomalidomide + Dexamethasone
    • Study PX171-004: Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma Cohort 1 20 mg/m2 Cohort 2† 20 mg/m2 cycle 1 Escalation to 27 mg/m2 in all subsequent cycles Carfilzomib IV QD x 2 for 3 weeks (28-day cycle for up to 12 cycles BOR-treated* (n=35) BOR-naïve (n=59) BOR-naïve (n=70) Study Population (N=165) • Measurable disease • Responsive to ≥1 prior therapy • Relapsed and/or refractory MM following 1–3 prior treatment regimens • ECOG PS 0–2 Vij et al, Blood: 119(24):5661-70, 2012 ORR (CR+VGPR+PR) 42.4% 52.2% 47.6% CBR (ORR+MR) 59.3% 64.2% 61.9% Cohort 1 Cohort 2 TotalBortezomib Naive
    • Cohort 1 20 mg/m2 Cohort 2† 20 mg/m2 cycle 1 Escalation to 27 mg/m2 in all subsequent cycles Study PX171-004: Phase 2 Trial of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma Duration of Clinical Benefit Resp. (med. Months) 11.5 NR Time to Clinical Benefit Response (med. months) 1.9 0.5 Time to Response (med. months) 1.0 0.5 Duration of Remission (med. Months) 13.1 NR Median TTP (med. Months) 8.3 NR Vij et al, Blood: 119(24):5661-70, 2012
    • History of Neuropathy at Baseline 69.8% Treatment Emergent Peripheral Neuropathy (all but 1pt Gr I or II in both studies) 17.1% Median QOL FACT-GOG No Change Grade 1 or 2 Neuropathy at Study Entry 53% Phase 2 Trials of Single-agent Carfilzomib in Relapsed and/or Refractory Multiple Myeloma 15.2% 87% PX-171-004 Bortezomib Naive PX-171-003-A0 Bortezomib Exposed Vij et al, Blood: 119(24):5661-70, 2012 Jagannath et al,, Clinical lymphoma, myeloma & leukemia. 12(5):310-8, 2012
    • Grade 1 Neuropathy 51% 0 0 Grade 2 Neuropathy 29% Phase 1 Trial of Pomalidomide in Relapsed and/or Refractory Multiple Myeloma Pomalidomide 2 mg po daily Pomalidomide 4 mg po daily Lacy et al, Blood 118(11): 2970-2975, 2011 Grade 3 Neuropathy Grade 4 Neuropathy 69% 3% 0 17%
    • Low Neuropathic Novel Agents Elotuzumab Doxorubicin/ Liposomal Doxorubicin* Pomalidomide? Bendamustine Low Neuropathic Conventional Agents Steroids Carfilzomib* Cyclophosphamide Dexamethasone Lenalidomide Melphalan Prednisone Potential Low Neuropathic Complications * Combination of carfilzomib with anthracyclines has not been reported; because of potential cardiac effects with carfilzomib this combination should be avoided based on lack of data Use of these combinations outside a clinical trial should be limited to those with previously reported results.
    • Case 3 This Patient: Carfilzomib at Relapse Thalidomide + Dexamethasone HDM + AuSCT Carfilzomib
    • Case 4 • 57 yr old female • 7/2012: Right Hip X-rays show lytic lesion right femur • Cytogenetics 46XX, FISH negative for high-risk • Hgb 9.8 g/dL, Plt 251 k/μL , WBC 6.8 k/μL, creatinine 0.7 mg/dL, Ca++ 9.1 mg/dL, albumin 3.0 M-protein 5.3 g/dL, IgA λ, Bence Jones Protein 98 mg/day, free λ 65 mg/L free κ 1.6 mg/L free κ: λ 0.01, β2M 7.2 mg/L Alb 3.0g/dL: ISS stage III • Bone survey: lytic lesions skull, ribs, femur • Bone marrow 17% CD38, CD138, CD56, λ +, κ – PC
    • Case 4 VRD Myeloablative therapy + AuSCT M-Protein(g/dL) Months 1 2 3 4 5 6 7 1 2 3 4 5 6 Lenalidomide 10 mg Maint.
    • Case 4M-Protein(g/dL) Months 1 2 3 4 5 6 7 1 2 3 4 5 6 VRD Myeloablative therapy + AuSCT Lenalidomide 10 mg Maint. M-Protein 1.6g/dL BM: 56% plasma cells Cytogenetics: t(4;14)
    • Case 4: What would you use for relapse? 2. Bortezomib-based 3-drug regimen 3. Myeloablative therapy and Autologous SCT 4. Allogeneic SCT 5. Clinical Trial 1. Lenalidomide-based 3-drug regimen
    • Bortezomib + High – Dose Melphalan (HDM) for Early Transplant Relapse and High-Risk Myeloma Wong Doo et al. Leukemia & Lymnphoma 2012; online HDM + BORTEZOMIB Stem Cell Harvest: Cyclophosphamide + G-CSF (usually collected before transplant 1) Day -2: Melphalan 200mg/M2 IV (RI:Melphalan 140mg/M2 IV) Day -1: Bortezomib 1.3 – 1.6 mg/M2 IV) Day 0: Stem cells infused Day 1 + Day 4: 2 pts Bortezomib 1.3 – 1.6 mg/M2 IV Day 2: 12 pts: Bortezomib 1.3 – 1.6 mg/M2 IV HDM Stem Cell Harvest: Cyclophosphamide + G-CSF (usually collected before transplant 1) Day -2: Melphalan 200mg/M2 IV (RI:Melphalan 140mg/M2 IV) Day 0: Stem cells infused N=16 PTS: Relapsed or Refractory 2nd Salvage N=16 PTS: Historical Control Relapsed or refractory > MR VGPR Med. PFS Med. OS Med. OS Early relapse 81.3% 37.5% 7 mos 28 mos 14.5 mos p 0.22 p 0.22 p 0.299 21 mos p 0.11 8 mos p 0.522 87.5% 12.5% 7 mos
    • Allogeneic Stem Cell TransplantPFS or EFS Benefit Overall Survival IFM: Garban et al Blood 2006 (High-Risk del 13, B2M > 3) No No EFS Benefit Yes OS Benefit Auto – RIC Allo SCT Vs. Auto-Auto Italian: Bruno et al Blood 2010 (No risk stratification) No 3yr PFS Benefit NoBMT CTN: Krishnan et al, Lancet Oncol (High-Risk del 13, B2M > 3) 5Yr YesBjorkstrand et al J Clin Oncol, 2011 (High-Risk del 13, B2M > 3)
    • Allogenic hematopoietic stem‐cell transplantation with reduced‐intensity conditioning in patients with refractory and recurrent multiple myeloma Shimoni et al, Cancer 116 (15): 3621-3630, 5 MAY 2010 DOI: 10.1002/cncr.25228 SCT from a female donor to a male achievement of a CR. occurrence of chronic GVHD Chemoresistance at the time of SCT Bad Risk Good Risk
    • Myeloma Section Robert Orlowski, MD Raymond Alexanian, MD Jatin Shah, MD Sheeba Thomas, MD Michael Wang, MD Department of Blood and Marrow Transplantation Richard Champlin , MD Muzaffar Qazilbash, MD Simrit Parmar, MD Uday Popat, MD Nina Shah, MD Thank you to the nurses, research staff and most importantly, the patients!